A sizeable fraction of the pharmaceutically active substances that is commercially available at present is very poorly soluble in water. As a result of this poor water solubility these pharmaceutically active substances are badly absorbed across mucosal barriers in e.g. the intestines and the mouth. This is why essentially water-insoluble pharmaceutically active substances are usually administered parenterally, e.g. intravenously, subcutaneously or intramuscularly. Since, however, these parenteral methods of administration are laborious and less suited for self-administration, efforts have been made by the pharmaceutical industry to find ways to deliver water-insoluble pharmaceutically active substances through a more convenient mode of administration, e.g. orally, sublingually or buccally.
It has been well recognised in the art of pharmacology that transmucosal absorption of water-insoluble substances can be enhanced significantly by providing these substances in the form of a very fine dispersion (e.g. an aqueos micro-emulsion) or by reducing the particle size of solid pharmaceutically active substances (e.g. by micronisation). In addition, the pharmaceutical industry has developed so called self-emulsifying preparations that spontaneously form a fine dispersion when contacted with water. Such self-emulsifying preparations may suitably be delivered via the oral mucosa (sublingual or buccal administration) or via the intestinal mucosa (e.g. oral administration).
Examples of water-insoluble pharmaceutically active substances include cannabinoids and particular classes of alkaloids. Cannabinoids are the active constituents of cannabis. Alkaloids occur as secondary metabolites in plants, animals (e.g. shellfish) and fungi. Many cannabinoids and alkaloids have demonstrable pharmacological effects in animals such as humans.
Cannabinoids, which are substituted meroterpenes are the major active constituents of the plant Cannabis sativa. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (Δ9-THC); others include the non-psychoactive (but pharmaceutically active) compounds cannabidiol (CBD) and cannabigerol (CBG). Cannabinoids can be administered by a variety of routes. Because of their high lipid solubility, topical administration is possible in such locations as the eye or the nasal mucosa. However, this has been of very limited applicability, because preparations of THC available in the past tended to be irritating to the eye. However, newer vehicles that permit lipid-soluble materials to be applied to the eye in aqueous solution may make this route of greater interest again.
In theory, percutaneous absorption, as from a drug-impregnated skin patch, should be possible, but the absorption would be very slow and not clinically useful.
Oral administration results in a slow and variable absorption, with a bioavailability of 10-20%, and usually less than 15%. Intravenous injection or infusion is possible, but because of the very low water-solubility of cannabinoids a special formulation must be used, such as a complex of the cannabinoid with plasma protein, or a solution in a water-miscible organic solvent. Intravenous administration of suitable preparations gives a very rapid onset of action, but because of dosage limitations to avoid excessive intensity of the peak effect, the duration of action is short.
Smoking is undoubtedly the best-known method of administration, and is the typical manner of using crude marijuana, as opposed to pure cannabinoids. Much of the total THC in crude cannabis is not free THC but tetrahydrocannabinolic acid. The heat just ahead of the advancing zone of combustion in a cigarette or pipeful of cannabis converts the THC acid to free THC, and volatilizes the THC so that it can be inhaled with the smoke, deep into the lung. The high lipid-solubility of the THC allows it to cross the alveolar membrane rapidly, entering the blood in the pulmonary capillaries. From here it is carried rapidly to the heart and pumped directly to the brain, so that the onset of action is at least as rapid as with intravenous injection.
What has been said above in relation to cannabinoids also applies by and large to many water-insoluble pharmaceutically active alkaloids and steroids. Alkaloids are usually classified by ether molecular feat, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, or by the plant or animal they were isolated from. When more is learned about a certain alkaloids, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically important amine that stands out in the synthesis process.
A steroid is a terpenoid lipid characterized by a carbon skeleton with four fused rings, generally arranged in a 6-6-6-5 fashion. Steroids can vary by the functional groups attached to these rings and the oxidation state of the rings. Hundreds of distinct steroids are found in plants, animals, and fungi. All steroids are biosynthetically derived either from the sterol lanosterol (animals and fungi) or the sterol cycloartenol (plants). Both sterols are derived from the cyclization of the triterpene squalene. Examples of pharmaceutically active steroids includes estrogens, progestogens, androgens.
Oral mucosal delivery offers several distinct advantages over other administration routes. The mouth is easily accessible with a wide aperture and a broad mucosal surface. The medication can pass easily into the reticulated veins that lie under the oral mucosa. The oral mucosa has more lipophilic cells than other mucosae, allowing for the delivery of lipophilic medications. It is found that medication absorbed through the buccal mucosa enters the circulation 4 to 8 times more rapidly than when it is ingested in pill or capsule form. Effects can be observed in 5-20 minutes compared to 30-60 minutes by ingestion into the stomach. Oral transmucosal delivery is also 20-30 times faster than transdermal (skin patch) delivery. Medication is more easily absorbed through the oral mucosa than through skin or rectal mucosa. Medication placed in the mouth is more acceptable to patients and more easily controlled than medication placed in the rectum, urethra, vagina, bladder, or up the nose.
GB 2 380 129 describes a pharmaceutical formulation for use in administration of a lipophilic medicament via a mucosal surface, which formulation comprises at least one lipophilic medicament and at least one self emulsifying agent, wherein upon hydration the formulation forms an emulsion containing the lipophilic medicament which is capable of adhering to a mucosal surface and allowing controlled release of the medicament. Also described are pharmaceutical formulation in the form of a gel or a compressed tablet for administration of a lipophilic medicament via the sublingual and/or buccal mucosa, wherein on contact with saliva the tablet or gel forms an emulsion containing the lipophilic medicament that adheres reversibly to the sublingual and/or buccal mucosa. Example 6 of the British patent application describes the preparation of a tablet for buccal or sublingual administration by dissolving glyceryl monostearate, polysorbate 80, ascorbyl palmitate and α-tocopherol and THC in alcohol, spraying the alcoholic solution onto a powder mix consisting of lactose and soluble starch, evaporating the alcohol, dusting the resulting granulate with talc and compressing to a target tablet weight of 101 mg.
Oral administration is generally seen as the most convenient mode of administration. Oral bioavailability, however, is greatly affected by the extent to which the pharmaceutically active substance is absorbed across the intestinal mucosa and the extent to which said substance is metabolised in the liver during the so called first pass.
Pulmonary administration via the respiratory system is also considered an efficient way of delivering pharmaceutically active substances. Administration occurs through inhalation of a nebula or aerosol carrying the active compound which can be taken up via the alveoli (lung).
WO 01/37808 describes solid pharmaceutical composition for improved delivery of hydrophilic or hydrophobic pharmaceutically active ingredients, said composition comprising a solid carrier that contains a substrate and an encapsulation coat on the substrate, wherein the encapsulation coat comprises at least one pharmaceutically active ingredient and at least one hydrophilic surfactant. The hydrophilic surfactant preferably is a surfactant having an HLB value of at least 10 or an ionic surfactant. It is stated in WO 01/37808 that the pharmaceutical composition can be formulated for oral, nasal, ocular, urethral, buccal, transmucosal, vaginal, topical or rectal delivery. It is further observed that hydrophilic surfactants can be used to provide increased solubility of the active ingredient in the solid carrier; improved dissolution of the active ingredient; improved solubilization of the active ingredient upon dissolution; enhances absorption and/or bioavailability of the active ingredient, particularly a hydrophilic active ingredient; and improved stability, both physical and chemical, of the active ingredient.